Zhong Zhi, Lemasters John J
Department of Cell and Developmental Biology, CB# 7090, 236 Taylor Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Alcohol. 2004 Aug;34(1):49-58. doi: 10.1016/j.alcohol.2004.08.006.
Alcohol is associated with accidental deaths and suicides leading to organ donation, and hepatic steatosis is an important risk factor for initial poor function and failure of human liver grafts. Mechanisms of fatty graft failure are not fully understood, but increased oxidative stress may be a major factor. To characterize the role of free radical stress and the efficacy of antioxidant treatments in fatty liver graft injury, donors for orthotopic rat liver transplantation were treated chronically (3 or more weeks) and acutely (single dose) with ethanol. After transplantation, necrosis and alanine aminotransferase release were threefold to fourfold higher in recipients of fatty grafts from donors treated with ethanol either acutely or chronically compared with findings for recipients of grafts from untreated donors. Moreover, graft survival decreased from nearly 100% to less than 20%. Free radical adducts, as measured by electron spin resonance spectroscopy, were detected in the blood and bile of rats receiving fatty grafts caused by ethanol. Markers of lipid peroxidation also increased after transplantation. Destruction of Kupffer cells with gadolinium chloride decreased free radical production and improved graft survival. Leukocyte adhesion increased beginning early after implantation, and adherent white blood cells obtained from transplanted fatty livers produced the same free radical species as were detected in blood. Therefore, Kupffer cells and adherent white blood cells are important sources of free radicals. Free radicals not only damage fatty grafts directly but also lead to enhanced inflammation and disturbed microcirculation. Delivery of superoxide dismutase-1 and superoxide dismutase-2 genes, free radical-scavenging polyphenols, and antioxidant-containing Carolina Rinse solution reduced injury and improved survival of fatty grafts caused by ethanol. Taken together, these findings indicate that free radicals increase in fatty grafts after transplantation and play an important role in injury of fatty grafts obtained from ethanol-exposed donors. Treatment of fatty donor livers with antioxidants and free radical scavengers may thus be an effective clinical therapy to prevent failure of fatty grafts.
酒精与导致器官捐献的意外死亡和自杀有关，肝脂肪变性是人类肝脏移植物初始功能不良和衰竭的重要危险因素。脂肪移植物衰竭的机制尚未完全明确，但氧化应激增加可能是一个主要因素。为了明确自由基应激在脂肪肝移植物损伤中的作用以及抗氧化治疗的效果，对原位大鼠肝移植的供体进行长期（3周或更长时间）和急性（单次剂量）乙醇处理。移植后，与未处理供体的移植物受体相比，急性或长期接受乙醇处理的供体的脂肪移植物受体的坏死和丙氨酸转氨酶释放高出三到四倍。此外，移植物存活率从近100%降至不到20%。通过电子自旋共振光谱法检测发现，接受乙醇所致脂肪移植物的大鼠血液和胆汁中存在自由基加合物。移植后脂质过氧化标志物也增加。用氯化钆破坏枯否细胞可减少自由基产生并提高移植物存活率。植入后早期白细胞黏附增加，从移植的脂肪肝中获取的黏附白细胞产生与血液中检测到的相同的自由基种类。因此，枯否细胞和黏附白细胞是自由基的重要来源。自由基不仅直接损伤脂肪移植物，还会导致炎症增强和微循环紊乱。超氧化物歧化酶-1和超氧化物歧化酶-2基因、自由基清除多酚以及含抗氧化剂的卡罗来纳冲洗液的递送可减轻乙醇所致脂肪移植物的损伤并提高其存活率。综上所述，这些发现表明移植后脂肪移植物中的自由基增加，并且在乙醇暴露供体的脂肪移植物损伤中起重要作用。因此，用抗氧化剂和自由基清除剂处理脂肪供体肝脏可能是预防脂肪移植物衰竭的一种有效临床疗法。
